tbuckley/cabot-search huggingface dataset:
Recent advances in targeted therapies in acute myeloid leukemia
Authors: Rahul S. Bhansali, Keith W. Pratz, Catherine Lai
Journal: Journal of Hematology & Oncology (2023)

Abstract Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.
Impact of FLT3-ITD location on cytarabine sensitivity in AML: a network-based approach
Authors: Giusj Monia Pugliese, Veronica Venafra, Valeria Bica, Giorgia Massacci, Sara Latini, Simone Graziosi, Thomas Fischer, Dimitrios Mougiakakos, Martin Boettcher, Livia Perfetto, Francesca Sacco
Journal: Leukemia (2023)
End of a Declared Public Health Emergency — Implications for U.S. Emergency Use Authorizations
Authors: Peter W. Marks, Hilary D. Marston, Lindsey R. Baden
Journal: New England Journal of Medicine (2023)

Interview with Dr. Peter Marks on the FDA's experience with emergency use authorizations during the Covid-19 pandemic. (06:13)Download Despite the planned ending of the Covid-19 public health emergency in the United States, medical products approved under emergency use authorizations will remain available for the foreseeable future.
The function and mechanisms of action of circular RNAs in Urologic Cancer
Authors: Zi-hao Zhang, Yue Wang, Ya Zhang, Sheng-Feng Zheng, Tao Feng, Xi Tian, Mierxiati Abudurexiti, Zhen-Da Wang, Wen-Kai Zhu, Jia-Qi Su, Hai-Liang Zhang, Guo-Hai Shi, Zi-Liang Wang, Da-Long Cao, Ding-Wei Ye
Journal: Molecular Cancer (2023)

Abstract Kidney, bladder, and prostate cancer are the three major tumor types of the urologic system that seriously threaten human health. Circular RNAs (CircRNAs), special non-coding RNAs with a stabile structure and a unique back-splicing loop-forming ability, have received recent scientific attention. CircRNAs are widely distributed within the body, with important biologic functions such as sponges for microRNAs, as RNA binding proteins, and as templates for regulation of transcription and protein translation. The abnormal expression of circRNAs in vivo is significantly associated with the development of urologic tumors. CircRNAs have now emerged as potential biomarkers for the diagnosis and prognosis of urologic tumors, as well as targets for the development of new therapies. Although we have gained a better understanding of circRNA, there are still many questions to be answered. In this review, we summarize the properties of circRNAs and detail their function, focusing on the effects of circRNA on proliferation, metastasis, apoptosis, metabolism, and drug resistance in kidney, bladder, and prostate cancers.
Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment
Authors: Ruiwen Ruan, Li Li, Xuan Li, Chunye Huang, Zhanmin Zhang, Hongguang Zhong, Shaocheng Zeng, Qianqian Shi, Yang Xia, Qinru Zeng, Qin Wen, Jingyi Chen, Xiaofeng Dai, Jianping Xiong, Xiaojun Xiang, Wan Lei, Jun Deng
Journal: Molecular Cancer (2023)

Abstract Background Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. Main Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling. Conclusion Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the “cancer-immune cycle”.
Relationship between comorbidities, mutational profile, and outcome after intensive chemotherapy in patients older than 60 years with acute myeloid leukemia: Assessment of different risk scores
Authors: Amélie Bachelot, Anne Bouvier, Jérémie Riou, Sylvain Thepot, Aurélien Giltat, Christopher Nunes Gomes, Jérôme Paillassa, Rébecca Jouanneau‐Courville, Maxime Renard, Annaelle Beucher, Laurane Cottin, Margaux Wiber, Bénédicte Ribourtout, Franck Geneviève, Damien Luque Paz, Aline Tanguy‐Schmidt, Valérie Ugo, Mathilde Hunault‐Berger, Odile Blanchet, Corentin Orvain
Journal: American Journal of Hematology (2023)

The aim of this study was to evaluate how comorbidities and molecular landscape relate to outcome in patients with acute myeloid leukemia (AML) aged 60 years or older who received intensive induction therapy. In 91 patients, 323 mutations were identified in 77 genes by next-generation sequencing, with a median of four mutations per patient, with NPM1, FLT3, TET2, and DNMT3A being the most frequently mutated genes. A multistate model identified FLT3, IDH2, RUNX1, and TET2 mutations as associated with a higher likelihood of achieving complete remission while STAG2 mutations were associated with primary refractory disease, and DNMT3A, FLT3, IDH2, and TP53 mutations with mortality after relapse. Ferrara unfitness criteria and performance status were the best predictors of short-term outcome (area under the curve = 82 for 2-month survival for both parameters), whereas genomic classifications better predicted long-term outcome, with the Patel risk stratification performing the best over the 5-year follow-up period (C-index = 0.63 for event-free and overall survival). We show that most genomic prognostic classifications, mainly used in younger patients, are useful for classifying older patients, but to a lesser extent, because of different mutational profiles. Specific prognostic classifications, incorporating performance status, comorbidities, and cytogenetic/molecular data, should be specifically designed for patients over 60 years.
Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 <scp>U.S.</scp> cancer centers
Authors: Kevin A. David, Suchitra Sundaram, Seo‐Hyun Kim, Ryan Vaca, Yong Lin, Samuel Singer, Mary‐Kate Malecek, Jordan Carter, Adam Zayac, Myung Sun Kim, Nishitha Reddy, Douglas Ney, Alma Habib, Christopher Strouse, Jerome Graber, Veronika Bachanova, Sidra Salman, Jean Alyxa Vendiola, Nasheed Hossain, Mazie Tsang, Ajay Major, David A. Bond, Prashasti Agrawal, Angel Mier‐Hicks, Pallawi Torka, Priya Rajakumar, Parameswaran Venugopal, Stephanie Berg, Michael Glantz, Samuel A. Goldlust, Matthew Folstad, Pallavi Kumar, Thomas A. Ollila, Johnny Cai, Stephen Spurgeon, Alex Sieg, Joseph Cleveland, Julie Chang, Narendranath Epperla, Reem Karmali, Seema Naik, Peter Martin, Sonali M. Smith, James Rubenstein, Brad Kahl, Andrew M. Evens
Journal: American Journal of Hematology (2023)

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.
Zinc‐Based Tannin‐Modified Composite Microparticulate Scaffolds with Balanced Antimicrobial Activity and Osteogenesis for Infected Bone Defect Repair
Authors: Yitao Zhao, Jintao Li, Lingli Liu, Yue Wang, Yan Ju, Chun Zeng, Zhihui Lu, Denghui Xie, Jinshan Guo
Journal: Advanced Healthcare Materials (2023)

Treatment of infected bone defects is a major clinical challenge; bioactive materials combining sufficient antimicrobial activity and favorable osteogenic ability are urgently needed. In this study, through a facile one-pot hydrothermal reaction of zinc acetate in the presence of tannic acid (TA), with or without silver nitrate (AgNO3 ), is used to synthesize a TA or TA and silver nanoparticles (Ag NPs) bulk-modified zinc oxide (ZnO) (ZnO-TA or ZnO-TA-Ag), which is further composited with zein to fabricate porous microparticulate scaffolds for infected bone defect repair. Bulk TA modification significantly improves the release rate of antibacterial metal ions (Zn2+ release rate is >100 times that of ZnO). Fast and long-lasting (>35 d) Zn2+ and Ag+ release guaranteed sufficient antibacterial capability and excellent osteogenic properties in promoting the osteogenic differentiation of bone marrow mesenchymal stem cells and endogenous citric acid production and mineralization and providing considerable immunomodulatory activity in promoting M2 polarization of macrophages. At the same time, synchronously-released TA could scavenge endogenous reactive oxygen species (ROS) and ROS produced by antibacterial metal ions, effectively balancing antibacterial activity and osteogenesis to sufficiently control infection while protecting the surrounding tissue from damage, thus effectively promoting infected bone defect repair.
Re: Alberto Gil-Jimenez, Jeroen van Dorp, Alberto Contreras-Sanz, et al. Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer. Eur Urol. 2023;83:313–7
Authors: Chunliang Cheng, Jiao Hu, Jinbo Chen
Journal: European Urology (2023)
Re: Clinical Efficacy of Neoadjuvant Intravesical Mitomycin-C Therapy Immediately Before Transurethral Resection of Bladder Tumor in Patients with Nonmuscle-invasive Bladder Cancer: Preliminary Results of a Prospective, Randomized Phase II Study
Authors: Marco Moschini, Andrea Salonia, Alberto Briganti, Francesco Montorsi
Journal: European Urology (2023)
Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling
Authors: Kezheng Peng, Chenye Zeng, Yuqi Gao, Binliang Liu, Liyuan Li, Kang Xu, Yuemiao Yin, Ying Qiu, Mingkui Zhang, Fei Ma, Zhao Wang
Journal: Acta Pharmaceutica Sinica B (2023)

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.
Plant–soil feedback under drought: does history shape the future?
Authors: Franciska de Vries, Jennifer Lau, Christine Hawkes, Marina Semchenko
Journal: Trends in Ecology & Evolution (2023)

Plant–soil feedback (PSF) is widely recognised as a driver of plant community composition, but understanding of its response to drought remains in its infancy. Here, we provide a conceptual framework for the role of drought in PSF, considering plant traits, drought severity, and historical precipitation over ecological and evolutionary timescales. Comparing experimental studies where plants and microbes do or do not share a drought history (through co-sourcing or conditioning), we hypothesise that plants and microbes with a shared drought history experience more positive PSF under subsequent drought. To reflect real-world responses to drought, future studies need to explicitly include plant–microbial co-occurrence and potential co-adaptation and consider the precipitation history experienced by both plants and microbes.
Incidence rates of childhood asthma with recurrent exacerbations in the US Environmental influences on Child Health Outcomes (ECHO) program
Authors: Rachel L. Miller, Holly Schuh, Aruna Chandran, Izzuddin M. Aris, Casper Bendixsen, Jeffrey Blossom, Carrie Breton, Carlos A. Camargo, Glorisa Canino, Kecia N. Carroll, Sarah Commodore, José F. Cordero, Dana M. Dabelea, Assiamira Ferrara, Rebecca C. Fry, Jody M. Ganiban, James E. Gern, Frank D. Gilliland, Diane R. Gold, Rima Habre, Marion E. Hare, Robyn N. Harte, Tina Hartert, Kohei Hasegawa, Gurjit K. Khurana Hershey, Daniel J. Jackson, Christine Joseph, Jean M. Kerver, Haejin Kim, Augusto A. Litonjua, Carmen J. Marsit, Cindy McEvoy, Eneida A. Mendonça, Paul E. Moore, Flory L. Nkoy, Thomas G. O’Connor, Emily Oken, Dennis Ownby, Matthew Perzanowski, Katherine Rivera-Spoljaric, Patrick H. Ryan, Anne Marie Singh, Joseph B. Stanford, Rosalind J. Wright, Robert O. Wright, Antonella Zanobetti, Edward Zoratti, Christine C. Johnson, P.B. Smith, K.L. Newby, L.P. Jacobson, D.J. Catellier, R. Gershon, D. Cella, A. Alshawabkeh, J. Aschner, S. Merhar, C. Ren, A. Reynolds, R. Keller, G. Pryhuber, A. Duncan, A. Lampland, R. Wadhawan, C. Wagner, M. Hudak, D. Mayock, L. Walshburn, S.L. Teitelbaum, A. Stroustrup, L. Trasande, C. Blair, L. Gatzke-Kopp, M. Swingler, J. Mansbach, J. Spergel, H. Puls, M. Stevenson, C. Bauer, S. Deoni, C. Duarte, A. Dunlop, A. Elliott, L. Croen, L. Bacharier, G. O’Connor, L. Bacharier, M. Kattan, R. Wood, G. Hershey, D. Ownby, I. Hertz-Picciotto, A. Hipwell, M. Karagas, C. Karr, A. Mason, S. Sathyanarayana, B. Lester, B. Carter, C. Neal, L. Smith, J. Helderman, L. Leve, J. Ganiban, J. Neiderhiser, S. Weiss, R. Zeiger, R. Tepper, K. Lyall, R. Landa, S. Ozonoff, R. Schmidt, S. Dager, R. Schultz, J. Piven, H. Volk, R. Vaidya, R. Obeid, C. Rollins, K. Bear, S. Pastyrnak, M. Lenski, M. Msall, J. Frazier, L. Washburn, A. Montgomery, C. Barone, P. McKane, N. Paneth, M. Elliott, J. Herbstman, S. Schantz, C. Porucznik, R. Silver, E. Conradt, M. Bosquet-Enlow, K. Huddleston, N. Bush, R. Nguyen, T. O'Connor, M. Samuels-Kalow
Journal: Journal of Allergy and Clinical Immunology (2023)
Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis
Authors: Ang Cui, Bo Li, Michael S. Wallace, Anna L.K. Gonye, Christopher Oetheimer, Hailey Patel, Pierre Tonnerre, Jacinta A. Holmes, David Lieb, Brianna S. Yao, Aileen Ma, Kela Roberts, Marcos Damasio, Jonathan H. Chen, Daphnee Piou, Charles Carlton-Smith, Joelle Brown, Ravi Mylvaganam, Jeremy Man Hon Fung, Moshe Sade-Feldman, Jasneet Aneja, Jenna Gustafson, Eliana T. Epstein, Shadi Salloum, Cynthia Brisac, Ashraf Thabet, Arthur Y. Kim, Georg M. Lauer, Nir Hacohen, Raymond T. Chung, Nadia Alatrakchi
Journal: Journal of Hepatology (2023)
Modulating arousal to overcome gait impairments in Parkinson’s disease: how the noradrenergic system may act as a double-edged sword
Authors: Anouk Tosserams, Bastiaan R. Bloem, Kaylena A. Ehgoetz Martens, Rick C. Helmich, Roy P. C. Kessels, James M. Shine, Natasha L. Taylor, Gabriel Wainstein, Simon J. G. Lewis, Jorik Nonnekes
Journal: Translational Neurodegeneration (2023)

Abstract In stressful or anxiety-provoking situations, most people with Parkinson’s disease (PD) experience a general worsening of motor symptoms, including their gait impairments. However, a proportion of patients actually report benefits from experiencing—or even purposely inducing—stressful or high-arousal situations. Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight (USA) and ParkinsonNEXT (NL) cohorts, we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment. Crucially, these strategies differ along an axis of arousal—some act to heighten, whereas others diminish, overall sympathetic tone. Together, our observations suggest that arousal may act as a double-edged sword for gait control in PD. We propose a theoretical, neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals, while alleviating them in others. Specifically, we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system: namely, that arousal is related to task performance by an inverted u-shaped curve (the so-called Yerkes and Dodson relationship). We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression, by regulating arousal and by mediating network-level functional integration across the brain. The ability of the locus coeruleus to facilitate dynamic ‘cross-talk’ between distinct, otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD. In the presence of suboptimal arousal, compensatory networks may be too segregated to allow for adequate compensation. Conversely, with supraoptimal arousal, increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional. Because the locus coeruleus degenerates with disease progression, finetuning of this delicate balance becomes increasingly difficult, heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub- or supraoptimal state of arousal to improve gait performance. Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.
Cross-cultural adaptability of parenting interventions designed for childhood behavior problems: A meta-analysis
Authors: Laura Maciel, Aitana Gomis-Pomares, Crispin Day, Miguel Basto-Pereira
Journal: Clinical Psychology Review (2023)

The dissemination of parenting interventions is one of the advised approaches to globally counteract childhood behavior problems, delinquency, and future criminal careers. Many of these interventions are developed in Anglosphere countries and transported to other contexts with distinct cultural backgrounds. However, there are no meta-analyses evaluating the overall effectiveness of these Anglosphere parenting programs in non-Anglosphere settings. This meta-analysis aimed to examine the effectiveness of parenting interventions developed in Anglosphere countries when transported to non-Anglosphere countries, as well as compare effectiveness levels between Anglosphere and non-Anglosphere trials; and analyze the impact of research and contextual factors in the dissemination of these interventions. Parenting interventions were included if they were: created in an Anglosphere setting; tested in non-Anglosphere countries; focused on reducing childhood behavioral problems; designed for children ranging from two to 12 years old; and tested in an experimental randomized trial. A random-effects model was selected for our meta-analysis. Standardized mean differences, confidence intervals and prediction intervals were also computed. Twenty studies were included, and results suggest that parenting interventions designed for childhood behavior problems can be transported to non-Anglosphere countries and potentially maintain effectiveness. This study is a relevant contribution to the evidence of cross-cultural transportability of parenting interventions.